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University of Birmingham Obeticholic Acid for the Treatment of Primary Biliary Cirrhosis University of Birmingham Obeticholic acid for the treatment of primary biliary cirrhosis Trivedi, Palak J; Hirschfield, Gideon M; Gershwin, M Eric DOI: 10.1586/17512433.2015.1092381 License: None: All rights reserved Document Version Peer reviewed version Citation for published version (Harvard): Trivedi, PJ, Hirschfield, GM & Gershwin, ME 2016, 'Obeticholic acid for the treatment of primary biliary cirrhosis', Expert Review of Clinical Pharmacology, vol. 9, no. 1, pp. 13-26. https://doi.org/10.1586/17512433.2015.1092381 Link to publication on Research at Birmingham portal Publisher Rights Statement: Eligibility for repository: Checked on 29/2/2016 General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. 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Oct. 2021 Expert Review of Clinical Pharmacology For Peer Review Only Obeticholic acid for t he treatment of primary biliary cirrhosis Journal: Expert Review of Clinical Pharmacology Manuscript ID: ERF-2015-0058.R1 Manuscript Type: Drug profiles Primary biliary cirrhosis, obeticholic acid, autoimmune disease, cholangitis, Keywords: ursodeoxycholic acid URL: https://mc.manuscriptcentral.com/erf Email: [email protected] Page 1 of 50 Expert Review of Clinical Pharmacology ^ƚĞƌĞŽŝƐŽŵĞƌƐ 1 2 3 4 5 6 7 8 9 10 11 12 For Peer Review Only 13 14 15 H H H 16 17 18 19 20 21ŐĞŶƚ KďĞƟĐŚŽůŝĐĂĐŝĚ ŚĞŶŽĚĞŽdžLJĐŚŽůŝĐĂĐŝĚ hƌƐŽĚĞŽdžLJĐŚŽůŝĐĂĐŝĚ 22 23 24 25WŽƚĞŶĐLJ 0.09 M 8.6 M EŽĂĐƟǀŝƚLJ 26 + + 27 ;&yZ50Ϳ 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] 50 51 52 53 54 55 56 57 58 59 60 Expert Review of Clinical Pharmacology Page 2 of 50 Bile acids Cholesterol 1 2 3 4 HEPATOCYTE 5 OCA 6 CYP7A1 FXR 7 SHP 8 9 BC 10 11 CDCA 12 For Peer Review Only 13 FXR 14 OCA CDCA NTCP 15 16 17 18 MDR3 BSEP 19 20 21 22 FGFR4 23 24 25 26 27 28 29 30 31 FGF19 32 33 34 35 36 ENTEROCYTE 37 38 39 FGF19 40 41 42 CDCA 43 CDCA ASBT CDCA 44 45 46 47 OST_ ` 48 I-BABP FXR 49 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] 50 51 OCA 52 53 54 55 56 57 58 59 60 APage 3 of 50 Expert ReviewB of Clinical Pharmacology Placebo dŝƚƌĂƟŽŶK;ŶсϳϬͿ 1 ϭϬŵŐK;ŶсϳϯͿ 2 60 3 0 4 * 5 * * 6 s 7 r 40 * 8 e d * 9 20 on * 10 p * * s * 11 e * 12 20 For Peer Review Only 13 % R 14 40 * * 15 * 16 й>WƌĞĚƵĐƟŽŶ * 17 0 18 0 6 12 19 6 months 12 months 20 Time (months) 21 C22 D 23 24 25 ϯ 26 27 0 28 2 29 30 * mol/L) * 31 + * * 32 1 10 33 * 34 * * * * 0 35 AST (IU/L) * 36 6 20 * 37 * * 38 -1 39 Total Bilirubin ( 6 * 40 * * ϯϬ 41 -2 * 42 0 6 12 0 6 12 43 44 Time (months) Time (months) 45 46 47 48 49 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] 50 51 52 53 54 55 56 57 58 59 60 Expert Review of Clinical Pharmacology Placebo Page 4 of 50 A 0.5 0.2 1 dŝƚƌĂƟŽŶK;ŶсϳϬͿ 1 ϭϬŵŐK;ŶсϳϯͿ 2 3 4 0.0 5 0.0 0 6 7 8 -0.5 9 10 -0.2 -1 11 IgA (g/L) IgG (g/L) IgM (g/L) -1.0 12 For Peer Review Only 13 ** * 14 -0.4 -2 ** 15 * -1.5 *** *** 16 *** 17 *** 18 19 -2.0 *** -0.6 -3 20 Month 6 Month 12 Month 6 Month 12 Month 6 Month 12 21 22 23 24 25B 26 4 60 27 2 28 29 40 30 1 31 2 32 33 20 34 0 35 36 (pg/dL) 0 0 37 _ 38 -1 CRP (mg/dL) TNF 39 IL-12 (pg/mL) 20- 40 41 -2 42 -2 ** *** 40- 43 ** * 44 * ** 45 46 -3 *** -4 60- 47 Month 6 Month 12 Month 6 Month 12 Month 6 Month 12 48 49 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] 50 51 52 53 54 55 56 57 58 59 60 Page 5 of 50 Expert Review of Clinical Pharmacology A 1 2 йŝƐĐŽŶƟŶƵĞĚ 3 100 4 ) 5 % ( 80 6 e 7 c 8 60 ĚĞŶ 9 i c 10 n i 40 11 s Ƶ 12 t i 13 r 20 Ƶ 14 r P 15 0 16 17 PlaceboFor10 m Peerg 50 m Reviewg Only 18 19 B 20 Placebo 21 40 22 * dŝƚƌĂƟŽŶK;ŶсϳϬͿ 23 * 24 ϭϬŵŐK;ŶсϳϯͿ 25 * 26 ϯϬ 27 28 29 30 31 20 32 33 34 35 WƌƵƌŝƚƵƐƐĐŽƌĞ;ŵŵͿ 10 36 37 38 39 0 40 0 6 12 41 42 43 Time (months) 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] Expert Review of Clinical Pharmacology Page 6 of 50 1 2 3 Expert Review of Clinical Pharmacology 4 5 6 Drug profile 7 8 November 9 10 11 American English 12 13 Obeticholic Acid for the Treatment of Primary Biliary Cirrhosis 14 For Peer Review Only 15 Palak J. Trivedi 1, Gideon M. Hirschfield 2 and M. Eric Gershwin 3 * 16 17 18 19 20 21 22 1NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, 23 24 2 3 25 United Kingdom; University of Birmingham, United Kingdom; Division of Rheumatology, 26 27 Allergy and Clinical Immunology, University of California at Davis, California, USA 28 29 30 31 32 [email protected] 33 34 [email protected] 35 36 37 [email protected] 38 39 40 41 *Corresponding author: M. Eric Gershwin, M.D., Division of Rheumatology, Allergy and 42 43 44 Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, 45 46 Davis, CA 95616 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] Page 7 of 50 Expert Review of Clinical Pharmacology 1 2 3 ABSTRACT 4 5 6 Primary biliary cirrhosis (PBC) is characterized by progressive non-suppurative destruction of 7 8 small bile ducts resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver 9 10 11 disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival; 12 13 although approximately one-third of all patients fail to achieve biochemical response, signifying 14 For Peer Review Only 15 a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of 16 17 18 the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid 19 20 synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic 21 22 regeneration in pre-clinical studies. Data from recent phase II and phase III controlled trials 23 24 25 suggests a therapeutic impact of OCA in PBC biochemical non-responders, as evidenced by 26 27 change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a 28 29 common adverse effect, but may be overcome through dose-titration. Longer-term studies are 30 31 32 needed with focus on safety and long-term clinical efficacy. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 URL: https://mc.manuscriptcentral.com/erf Email: [email protected] Expert Review of Clinical Pharmacology Page 8 of 50 1 2 3 Introduction 4 5 6 Primary biliary cirrhosis (PBC) is an immune-mediated hepatobiliary disorder characterised by 7 8 ductopenia, chronic cholestasis and progressive liver fibrosis [1–4]. Although there are multiple 9 10 animal models proposed, often with similar immunological abnormalities as patients with PBC, 11 12 13 therapeutic efforts have thus far been based entirely on human clinical trials [5–9]. Presently, the 14 For Peer Review Only 15 mainstay of treatment is ursodeoxycholic acid (UDCA), which in addition to stimulating 16 17 hepatobiliary secretions is a potent intracellular signaling molecule, inducing choleresis through 18 19 20 mitogen-activated protein kinase (MAPK) and integrin-dependent mechanisms [10]; as well as 21 22 protecting epithelia from ‘toxic’ effects of low pH bile acids [11].
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